title: Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor.
abstract: The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: James
authors.initials: J
authors.lastname: Koh
authors.forename: Moahad
authors.initials: M
authors.lastname: Dar
authors.forename: Brian R
authors.initials: BR
authors.lastname: Untch
authors.forename: Darshana
authors.initials: D
authors.lastname: Dixit
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Shi
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: Mohamed Abdelgadir
authors.initials: MA
authors.lastname: Adam
authors.forename: Holly
authors.initials: H
authors.lastname: Dressman
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Robert
authors.initials: R
authors.lastname: Spurney
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.forename: John A
authors.initials: JA
authors.lastname: Olson
mesh_terms: D000236:Adenoma / Q000150:complications / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000097:blood; D002125:Calcium Gluconate / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010282:Parathyroid Neoplasms / Q000150:complications / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D010281:Parathyroid Hormone; D020710:RGS Proteins; C491349:RGS5 protein, human; D044169:Receptors, Calcium-Sensing; D002125:Calcium Gluconate; D002118:Calcium